Chemosensitivity of human colon cancer cells is influenced by a p53-dependent enhancement of ceramide synthase 5 and induction of autophagy
Chemosensitivity of human colon cancer cells is influenced by a p53-dependent enhancement of ceramide synthase 5 and induction of autophagy
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DOI：
10.1016/j.bbalip.2018.07.011
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发表时间：
2018-10-01
影响因子：
4.8
通讯作者：
Groesch, Sabine
中科院分区：
文献类型：
--
作者：
Brachtendorf, Sebastian;Wanger, Ruth Anna;Groesch, Sabine
对化疗的耐药性是结肠癌治疗中危及生命的并发症。为了提高缓解率，仍需要探索有助于化学耐药性的新的额外靶标。神经酰胺属于鞘脂类，分别是众所周知的细胞死亡和存活调节剂。在这里，我们发现，在人野生型 ((wt)) p53 HCT-116 结肠癌细胞中，用奥沙利铂或 5-氟尿嘧啶 (5-FU) 处理会导致神经酰胺合酶 5 (CerS5) 表达和 C-16:0-神经酰胺水平大幅增加，而在缺乏 p53 表达的 HCT-116 (HCT-116 p53(-/-)) 中未显示出这一点。 CerS5 表达的增加是通过稳定 3'-UTR 处的 CerS5 mRNA 来实现的。相比之下，在p53缺陷细胞中，CerS2表达以及CerS2相关的C-24:0-和C-24:1-神经酰胺水平升高，这可能与这些细胞中CerS2转录物的多腺苷酸化增强有关。使用CerS5靶向shRNA稳定敲低CerS5表达导致HCT-116 p53(wt)细胞对奥沙利铂和5-FU的敏感性增加，但p53(-/-)细胞不增加。敏感性的增强伴随着这些细胞中自噬和线粒体呼吸的抑制。然而，敲除CerS2对两种细胞系的化疗敏感性没有显着影响。 总之，在p53（wt）结肠癌细胞中，下调CerS5表达导致自噬和线粒体呼吸减少，可以增强对奥沙利铂或5-FU的化疗敏感性。
Resistance against chemotherapy is a life-threatening complication in colon cancer therapy. To increase response rate, new additional targets that contribute to chemoresistance are still needed to be explored. Ceramides, which belong to the group of sphingolipids, are well-known regulators of cell death and survival, respectively. Here, we show that in human wild-type ((wt)) p53 HCT-116 colon cancer cells treatment with oxaliplatin or 5-fluorouracil (5-FU) leads to a strong increase in ceramide synthase 5 (CerS5) expression and C-16:0-ceramide levels, which was not shown in HCT-116 lacking p53 expression (HCT-116 p53(-/-)). The increase in CerS5 expression occurs by stabilizing CerS5 mRNA at the 3'-UTR. By contrast, in the p53-deficient cells CerS2 expression and CerS2-related C-24:0- and C-24:1-ceramide levels were elevated which is possibly related to enhanced polyadenylation of the CerS2 transcript in these cells. Stable knockdown of CerS5 expression using CerS5-targeting shRNA led to an increased sensitivity of HCT-116 p53(wt) cells, but not of p53(-/-) cells, to oxaliplatin and 5-FU. Enhanced sensitivity was accompanied by an inhibition of autophagy and inhibition of mitochondrial respiration in these cells. However, knockdown of CerS2 had no significant effects on chemosensitivity of both cell lines.In conclusion, in p53(wt) colon cancer cells chemosensitivity against oxaliplatin or 5-FU could be enhanced by downregulation of CerS5 expression leading to reduced autophagy and mitochondrial respiration.